It was predicted that, in hibernating ground squirrels, the blood-brain barrier (BBB) to blood-borne horseradish peroxidase (HRP) could be opened with hyperosmotic solutions even though active, vesicular transport would be suppressed during hypothermia; the opening was expected to be by way of intracellular clefts. In 7 of l0 squirrels infused with the solution at a high flow rate, 2.9 ml over a 30 second period, some exudates formed. Could the high flow rate and pressure of injection have ruptered capillaries? When a slower rate, 90 seconds, was used, 5 of 7 animals had exudates. Moreover, there were no exudates in the brains of squirrels infused at the higher rate with isosmotic solutions. Therefore, the escape of HRP after hyperosmotic exposure of cerebral vessels was not due to endothelial damage. Although most of the animals had some exudates after the hyperosmotic treatment, the number was highly variable, so the barrier was opened by a second method: hypertension. Aramine or nor-epinephrine was given intravenously to 8 hypothermic squirrels and the arterial blood pressure elevated from 40 to 120 mm Hg. There were some exudates in 7 of these animals. Five additional squirrels were warmed to a body temperature of about 23 C. Of these, 3 had exudates. However, the variability in the number of exudates was sufficiently great to prohibit designating the number as "intermediate" between hypo- and normo-thermic brains. Instead of opening the BBB in rats, we bypassed it with a series of grafts into the cerebral cortex. Transplants of skeletal and cardiac muscle, skin, choroid plexus, omentum and superior cervical ganglion were compared. The greatest leak of blood-borne HRP into the surrounding brain with an intact BBB consistently occurred via the isografts of superficial neck muscle. The insertion of gel foam in the same area and to the same cortical depth did not lead to any discernible entry of protein.